Findings from the Diabetes Control and Complications Trial have shown that tight glycemic control, achieved through intensive insulin therapy, prevents and reduces the onset and progression of the complications associated with uncontrolled diabetes. To achieve this, a high level of patient self-care is critical. Patients with diabetes, however, are twice as likely to develop depression compared to the general population. For diabetic patients with co-morbid depression, diligent self-care and diabetes management can be profoundly impaired, resulting in a significantly greater risk of developing diabetes-related complications and morbidity. The commonly prescribed antidepressant class of selective serotonin reuptake inhibitors (SSRIs) has been associated with significant incidence of hypoglycemia. The mechanism(s) underlying this have not been elucidated. The proposed studies will test the hypothesis that the SSRIs may impair the ability of the brain to detect hypoglycemia by reducing the responsiveness of hindbrain glucose sensing neurons that are critical to hypoglycemia detection and activation of counterregulatory responses. The following hypotheses will be tested: I) Peripheral administration of SSRIs decrease the counterregulatory response to hypoglycemia and II) SSRIs delivered directly into the terminal fields of hindbrain glucose sensing neurons impair the counterregulatory response to hypoglycemia. To test these hypotheses we will administer sertraline, acutely or chronically, to non-diabetic Wistar rats and will measure the neuroendocrine counterregulatory response to a bout of hypoglycemia. Finally, patients with diabetes exhibit a significant increase in severe hypoglycemic episodes. Thus, we will test the hypothesis III) that SSRIs are more detrimental to counterregulation in diabetic vs. non-diabetic rats. The results of these studies will provide new knowledge that ultimately may assist primary physicians in determining the most advantageous treatment for their diabetic patients with depression.